Berillo D.A., Turmukhanova M.Zh., Abilov Zh.A., Ahmedova Sh. S.

Al-Faraby Kazakh National University, Almaty, Kazakhstan

Synthesis of derivatives of α-methyl-β-(N-piperidyl)-

propane acids

For a number of years we have conducted research work in the basic directions, connected with updating heterocyclic amines, by introduction of various the pharmacophore groups into their structure leading to the decrease in toxicity of compounds, to strengthening of the basic pharmacological effect and revealing of new kinds of biological activity.

In the present work for synthesis of potentially biologically active substances commercially available reagents, such as methyl and butyl ester of methacrylic acids, piperidine, hydroxylamine and 2,4-dinitrophenylhydrazine are used.

The presence of various functional groups in a piperidine cycle allows to use piperidine as basic synton in organic synthesis and to consider its derivatives as possible precursors of biologically active compounds. Availability of several electrophilic centers with different reactivities assumes numerous variants of interaction of such compounds with nucleophiles.

Synthesis of ester of α-methyl-β-(N-piperidyl)propane acids (1,2) is provided by nucleophilic addition of piperidine to methacrylic acid esters in alcohol solution, at the same time there proceeds a reaction of reesterification.

It is known that hydroxamic acids and metalorganic complexes of hydroxamic acid exhibit an inhibitor activity on α-chymotrypsin and other enzymes [1,2]. With the purpose of searching for potentially biologically active compounds α-methyl-β-(N-piperidyl)propane hydroxamic acid is obtained as a result of reaction of the methyl ester of α-methyl-β-(N-piperidyl)propane acid (1) with hydroxylamine in the presence of alkali in the water medium. It is well known that hydroxamic acids are characterized by keto-enol tautomerism [2]. So, in a crystal condition α-methyl-β-(N-piperidyl)propane hydroxamic acid mainly exists in keto- form (A), that has been proved on the basis of IR-spectroscopy by a characteristic absorption band of a carbonyl group at 1649 см^-1. As a consequence of spectrophotometric investigation it is stated that in water medium the compound (1) represents a mixture of tautomeric forms A and B.

Hydrazides of carbonic acids are used as in quality hardeners for epoxy pitches and also are successfully used in agriculture as herbicides, insecticides. Among hydrazine derivatives, the effective medicinal substances being used in medicine are known. Among antibacterial medicines there is a group of the antituberculosis means containing a hydrazides fragment [3, 4].

One of the general ways of synthesis of hydrazides is interaction of esters of carbonic acid with hydrazine hydrate. Hydrazide of α-methyl-β-(N-piperidyl)propane acid was obtained by condensation reaction of methyl or butyl esters of α-methyl-β-(N-piperidyl)propane acid (1,2) with hydrazidehydrate in ethanol medium. A primary biological screening for compound (4) has shown the following kinds of activity: spasmolitic, analgesic and antimicrobic. It has been stated that compound (4) possesses low toxicity (LD₅₀ 800 mg/kg) [5].

From literature data it is known that derivatives of nitrocompounds show high antimicrobic activity [3]. With the purpose of searching for an active medicine of a wide spectrum of action, we carried out synthesis of N¹-(2,4-dinitrophenyl)hydrazide of α-methyl-β-(N-piperidyl)propane acid (5) at condensation of 2,4-dinitrophenylhydrazine with a methyl ester α-methyl-β-(N-piperidyl)propane acid (1) in the presence of catalytic amounts of piperidine in the ethanol medium. Thus, functionalization of the methyl ester of α-methyl-β-(N-piperidyl)propane acid (1) was carried out in which resulted a combination of several pharmacophoric groups: the cycle of piperidine, hydrazide and nitro – groups in compound (5). The composition and the structure of the obtained compounds (1-5) were proved on the basis of data of IR- UV- NMR- spectroscopy and GH-MS.

References

1. A. Moulin, J. H. Bell, R.F. Pratt, D. Ringe. Inhibition of Chymotrypsin by a Complex of Ortho-Vanadate and Benzohydroxamic Acid: Structure of the Inert Complex and its Mechanistic Interpretation. 2007, Biochemistry, Vol. 46 (20), pp. 5982–5990.

2. K. Kobashi, N.Terashima, J. Hase. Spectrophotometric studies on hydroxamic acid-boronate and alumimate complex. 10, 1973, Chem. Pharm. Bull., Vol. 23, pp. 2303-2308.

3. M. D. Mashkovsky. Medical remedy. Kharkov: 1998. V. 1,2.

4. №21703 The innovative patent R.K. D.A. Berillo, Sh.S. Ahmedova, S.N. Shin, O.A. Berillo Hydrazide of 2-methyl-3-(N-piperidyl)propane acid possessing a spasmolitic, analgetic and antimicrobial activity. (15.09.2009), bulletin №9.